WO2011089267A1 - Biomolécules silylées - Google Patents

Biomolécules silylées Download PDF

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Publication number
WO2011089267A1
WO2011089267A1 PCT/EP2011/050981 EP2011050981W WO2011089267A1 WO 2011089267 A1 WO2011089267 A1 WO 2011089267A1 EP 2011050981 W EP2011050981 W EP 2011050981W WO 2011089267 A1 WO2011089267 A1 WO 2011089267A1
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WIPO (PCT)
Prior art keywords
silylated
biomolecule
hydrogel
acid
process according
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PCT/EP2011/050981
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English (en)
Inventor
Pierre Weiss
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Institut National De La Sante Et De La Recherche Medicale (Inserm)
Universite De Nantes
Chu Nantes
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Application filed by Institut National De La Sante Et De La Recherche Medicale (Inserm), Universite De Nantes, Chu Nantes filed Critical Institut National De La Sante Et De La Recherche Medicale (Inserm)
Priority to ES11701110.6T priority Critical patent/ES2627486T3/es
Priority to EP11701110.6A priority patent/EP2529226B1/fr
Priority to US13/574,970 priority patent/US9285360B2/en
Publication of WO2011089267A1 publication Critical patent/WO2011089267A1/fr

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    • G—PHYSICS
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
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    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
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    • C08G18/10—Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
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    • C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
    • C08G18/40—High-molecular-weight compounds
    • C08G18/64—Macromolecular compounds not provided for by groups C08G18/42 - C08G18/63
    • C08G18/6415—Macromolecular compounds not provided for by groups C08G18/42 - C08G18/63 having nitrogen
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    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
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    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
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    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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    • C08J2300/00—Characterised by the use of unspecified polymers
    • C08J2300/10—Polymers characterised by the presence of specified groups, e.g. terminal or pendant functional groups
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Definitions

  • the present invention relates to a process for the silylation of biomolecules, in particular for the preparation of hydrogels.
  • Hydrogels are used in many fields, namely as tissue substitute, for example bone substitute, or for ophthalmologic surgery.
  • tissue substitute for example bone substitute
  • ophthalmologic surgery The development of hydrogels presenting interesting properties in term of injectability, self-hardening and stability is therefore needed.
  • Bourges et al. (Advances in Colloid and Interface Science 99, 215-228, 2002) describe the preparation of a hydrogel made from silylated hydro soluble cellulose ether (HPMC). More precisely, silylated HPMC was synthesized by reaction of HPMC with 3-glycidoxypropyltrimethoxysilane (GPTMS). A hydrogel was then prepared by introducing the silylated HPMC in a basic medium, followed by a neutralisation. However, this method is a three-step procedure (premix of HPMC and NaOH, reaction with GPTMS and quench of the reaction with acetic acid) and requires a high reaction temperature (80-100 °C).
  • GPTMS 3-glycidoxypropyltrimethoxysilane
  • hydrogel based on silylated HPMC does not adhere well to hydrogel based on silylated HPMC. Said hydrogel is therefore not suited for cells requiring adhesion for their growth.
  • the development of new hydrogels that can be used for all kind of cells is therefore needed, in particular hydrogels based on a biomolecule different from HPMC.
  • biomolecule are temperature-sensitive, and would be destroyed or denatured by using the process based on GPTMS described above, which requires high reaction temperature.
  • the development of other silylated biomolecule allowing the production of hydrogels is therefore required.
  • the present invention provides silylated biomolecule usable to prepare a hydrogel.
  • the invention provides a silylated biomolecule having the following formula (I):
  • - A is a biomolecule chosen from a peptide, an oligopeptide, a protein, a deoxyribonucleic acid, a ribonucleic acid, pectin, chitosan, hyaluronic acid, and a glycolipid,
  • - m is an integer ranging from 1 to 6,
  • - p and q are independently 0 or 1 ,
  • - X is a group chosen from -NHCONH-, -OCONH- and -CONH-, and
  • R 2 and R 3 each independently represent a CrC 6 alkyl group.
  • the invention relates to the process for the preparation of said silylated biomolecule.
  • the invention concerns the use of a silylated biomolecule to functionalize the surface of a support.
  • the invention concerns a process for the preparation of a hydrogel comprising the steps of:
  • step b) adjusting the pH of the aqueous medium of step a) to a pH of between 3.5 and 12.4, and optionally recovering the hydrogel.
  • the invention relates to the hydrogel obtainable by the process as described above.
  • the invention concerns the hydrogel as a biological tissue substitute.
  • the invention relates to a composition
  • a composition comprising a hydrogel as described above in a pharmaceutically acceptable vehicle.
  • the invention concerns said composition for the release of active principle.
  • silation means introduction of a silyl function into said biomolecule, more precisely an alkoxysilane function.
  • biomolecule means any organic molecule that is produced by a living organism or that is a derivative thereof, including large polymeric molecules such as proteins (natural or synthetic), polysaccharides (natural or synthetic), and nucleic acids as well as small molecules such as primary metabolites, secondary metabolites, and natural products.
  • biomolecules mention may be made of:
  • lipid derivatives such as phospholipids, glycolipids and sterols
  • sugar derivatives such as carbohydrate, disaccharide, oligosaccharides, polysaccharides (including cellulose),
  • amino acid derivatives such as amino acids (natural and/or non-standard), peptides, oligopeptides, polypeptides, proteins (said peptides, oligopeptides, polypeptides and proteins containing natural and/or non-standard aminoacid),
  • nucleotides derivatives such as nucleotides, and biological polymers such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA),
  • biopolymers such as lignin, proteins, DNA, RNA, oligosaccharides, polysaccharides.
  • the biomolecule is a polysaccharide, a protein, or a peptide.
  • polysaccharide means a polymer made up of many monosaccharides joined together by glycosidic bonds. Natural and synthetic polysaccharides are included. Examples of polysaccharide are cellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC), pectin, chitosan, hyaluronic acid.
  • protein means a polymer made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. Glycoprotein as well as proteins containing natural and/or non-standard aminoacid are included. Albumin, laminin, gelatin, fibronectin, vitronectin and collagen are examples of protein.
  • peptide means also a polymer made of amino acids arranged in a linear chain and joined together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. Peptides containing natural and/or nonstandard aminoacid are included. Generally, peptides contain less than 50 aminoacids whereas proteins contain more than 50. RGDS (Arg-Gly-Asp-Ser) is an example of peptide which can be used as a biomolecule in the present invention.
  • an alkyl is a branched or linear saturated hydrocarbon chain having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms.
  • hydrogel » means a network of polymer chains that are water-insoluble, in which water is the dispersion medium.
  • aqueous medium means a medium wherein water is the major solvent.
  • the invention provides a silylated biomolecule having the following formula (I):
  • - A is a biomolecule chosen from a peptide, an oligopeptide, a protein, a deoxyribonucleic acid, a ribonucleic acid, pectin, chitosan, hyaluronic acid, and a glycolipid,
  • - m is an integer ranging from 1 to 6,
  • - p and q are independently 0 or 1 ,
  • - X is a group chosen from -NHCONH-, -OCONH- and -CONH-, and
  • R 2 and R 3 each independently represent a C C 6 alkyl group.
  • a in the silylated biomolecule is chosen from a peptide, an oligopeptide, a protein, a deoxyribonucleic acid, a ribonucleic acid, pectin, hyaluronic acid, and a glycolipid. These biomolecules are indeed temperature-sensitive.
  • a in the silylated biomolecule is chosen from the group hyaluronic acid, pectin, collagen, gelatin, RGDS and chitosan.
  • the invention provides a process for the preparation of a silylated biomolecule as described above. Two processes are described therein, depending on whether the biomolecule used as starting material is carrying an amine or an alcohol function on the one hand (process 1 ), or a carboxylic acid function on the other hand (process 2).
  • the invention provides a process 1 for the preparation of a silylated biomolecule of formula (I) as described above, comprising the step of reacting a biomolecule carrying an alcohol or amine function, preferably chosen from a peptide, an oligopeptide, a protein, a deoxyribonucleic acid, a ribonucleic acid, pectin, chitosan, hyaluronic acid, a glycolipid with a silylation agent having the following formula (II):
  • - m is an integer ranging from 1 to 6,
  • - p and q are independently 0 or 1 , and
  • R 2 and R 3 each independently represent a CrC 6 alkyl group.
  • Silylated biomolecules of formula (I), wherein X is a -NHCONH- or a -OCONH- moiety are obtained by process 1 .
  • the amine or the alcohol function of the biomolecule reacts with the isocyanate function of the silylation agent of formula (II), leading to the formation of an urea bond (-NHCONH- ) (if the biomolecule is carrying an amine function) or a carbamate bond (-OCONH-)(if the biomolecule is carrying an alcohol function) according to the following scheme :
  • the biomolecule is carrying an alcohol function and is preferably chosen from a deoxyribonucleic acid, a ribonucleic acid, pectin, chitosan, hyaluronic acid, a glycolipid and optionally from a peptide, an oligopeptide, a protein, when said peptide, oligopeptide, or protein comprise a moiety (an amino acid for example) carrying an alcohol function, for example the RGDS.
  • the biomolecule is carrying an amine function and is preferably chosen from a peptide, an oligopeptide, a protein, a deoxyribonucleic acid, a ribonucleic acid and chitosan.
  • the biomolecule used in the process can also carry both an alcohol function and an amine function, for example when the biomolecule is chitosan.
  • the silylation agent used in the process is 3- isocyanatopropyltriethoxysilane.
  • the biomolecule when the biomolecule is carrying amine functions, part of said amine functions are not protonated in the reaction medium.
  • the lone pair of the amine has indeed to be available to attack the isocyanate function.
  • the temperature of the reaction of process 1 is not critical and may vary in wide range.
  • reaction is generally carried out at a temperature from -15°C to 40°C, preferably 0°C to 30°C, more preferably from 15°C to 25 q C, which is advantageous as no denaturation of biomolecule occurs.
  • process 1 is carried out under inert atmosphere, for example under argon or nitrogen.
  • the reaction time is usually lasts from one hour to one week, preferably from twelve hours to five days, more preferably from one to three days.
  • Process 1 is generally carried out in a solvent.
  • a solvent There is no particular restriction on the nature of the solvent to be used, provided that it has no adverse effect on the reaction or on the reagents involved.
  • process 1 is carried out in an anhydrous solvent, such as anhydrous acetonitrile, anhydrous acetone, anhydrous dimethylformamide or anhydrous dimethylsulfoxide, and in the presence of a base, preferably an organic base, usually an organic base containing a nitrogen atom which can be protonated, for example triethylamine, pyridine or trimethylamine.
  • an anhydrous solvent such as anhydrous acetonitrile, anhydrous acetone, anhydrous dimethylformamide or anhydrous dimethylsulfoxide
  • a base preferably an organic base, usually an organic base containing a nitrogen atom which can be protonated, for example triethylamine, pyridine or trimethylamine.
  • process 1 is carried out in a mixture comprising an aqueous solution and a solvent miscible in water, such as acetonitrile, acetone, dimethylformamide and dimethylsulfoxide.
  • the mixture is preferably a mixture of water and of dimethylsulfoxide. No base is required for this embodiment.
  • a second process is described therein, when the biomolecule used as starting material is carrying a carboxylic acid or a carboxylate function (process 2).
  • process 2 provides a process for the preparation of a silylated biomolecule of formula (I) as defined above, comprising the steps consisting of:
  • a biomolecule carrying a carboxylic acid or a carboxylate function preferably chosen from a peptide, an oligopeptide, a protein, pectin, hyaluronic acid, with 1 -ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCI) or with 1 ,1 '- carbonyldiimidazole (CDI), then
  • step b) adding to the reaction medium obtained in step a) a silylation agent having the following formula (III):
  • - n is an integer ranging from 1 to 6
  • - p and q are independently 0 or 1 , and
  • R 2 and R 3 each independently represent a C C 6 alkyl group.
  • Silylated biomolecules of formula (I), wherein X is a -CONH- moiety are obtained by process 2.
  • the carboxylic function of the biomolecule is activated with EDC.HCI in step a) and then reacts with the amine function of the silylation agent of formula (III), leading to the formation of an amide bond (-CONH-) according to the following scheme :
  • Prefered biomolecule used as starting material in step a) of process 2 are a peptide, an oligopeptide, a protein, pectin, and hyaluronic acid.
  • Step a) of process 2 can be carried out in the presence of a catalyst, such as N- hydroxysuccinimide.
  • the silylation agent used in step b) of process 2 is preferably (3- aminopropyl)triethoxysilane.
  • steps a) and b) of process 2 are generally carried out in an aqueous solution, the pH of which is preferably from 4 to 6, most preferably from 4.7 to 5.3, preferably in water.
  • steps a) and b) of process 2 are generally carried out in dichloromethane or acetonitrile.
  • Steps a) and b) of process 2 are generally carried out at a temperature from -15°C to 40 ⁇ C, preferably 0 ⁇ C to 30 °C, more preferably from 15 ⁇ C to 25 ⁇ C, which is advantageous as no denaturation of biomolecule occurs.
  • Step a) of process 2 usually lasts from 4 h to 24h, preferably from 12 h to 18 h, and step b) of process 2 usually lasts from 4 h to 24h, preferably from 12 h to 18 h.
  • the weight concentration of the biomolecule used as starting material in the solvent in processes 1 and 2 is generally from 0,01 to 30%, preferably from 0,1 to 20%, more preferably from 0,5 to 15%.
  • processes 1 and 2 are carried out without any metal catalyst, more particularly tin based catalyst.
  • reaction medium When process 2 wherein EDC.HCI is used is carried out, the reaction medium is generally homogeneous. When process 1 or process 2 wherein CDI is used are carried out, the reaction medium is generally heterogeneous. A suspension of the biomolecule in the solvent is generally observed, which can be isolated easily from the reaction mixture, for example by sedimentation or centrifugation.
  • the invention concerns the use of said silylated biomolecule to functionalize the surface of a support.
  • the alkoxysilane functions ORi , OR 2 and OR 3 of the silylated biomolecule can advantageously be used to anchor the silylated biomolecule to the surface of a support.
  • the surface can be any surface of a support able to react with an alkoxysilane function, for example a metal surface such as titanium surface or a glass surface.
  • the invention concerns a process for the preparation of a hydrogel comprising the steps of:
  • step b) adjusting the pH of the aqueous medium of step a) to a pH of between 3.5 and 12.4, and optionally recovering the hydrogel.
  • the aqueous medium of step a) comprises an aqueous solution and the silylated biomolecule, which can be soluble or not in the aqueous solution.
  • step a Two embodiments are possible for step a), depending if a base or an acid is used.
  • the silylated biomolecule is contacted with a base in an aqueous medium during step a)
  • the alkoxysilane function of the silylated biomolecule is hydrolyzed into a silanolate function.
  • Adjusting the pH of the mixture thus obtained leads to protonation of the silanolate function to give silanol function, which will inherently react with another silanol function, leading to the condensation of the silylated biomolecules via the formation of -Si-O-Si- covalent bond, and hence to the formation of the hydrogel.
  • an inorganic base is used in step a), more preferably an alkaline or alkaline earth metal hydroxide, such as potassium or sodium hydroxide.
  • the pH of the aqueous medium during step a) is from 12 to 14, preferably from 12.3 to 12.9.
  • the silylated biomolecule is contacted with an acid in an aqueous medium during step a), typically in an aqueous medium the pH of which is from 1 to 3, preferably around 2, for example in a HCI solution or a HEPES solution.
  • the alkoxysilane function of the silylated biomolecule is hydrolyzed into a silanol function, which will inherently react with another silanol function, leading to the condensation of the silylated biomolecules via the formation of — Si-O-Si- covalent bond, and hence to the formation of the hydrogel.
  • This embodiment is particularly suited for silylated biomolecule, wherein the biomolecule is a peptide, an oligopeptide, a protein, or hyaluronic acid.
  • the process for the preparation of a hydrogel is advantageously based on auto- condensation of silanol functions just by adjusting the pH, without requiring toxic additives to be added.
  • step a) of the process for the preparation of a hydrogel is preferred.
  • step a) lasts from 10 minutes to three days, preferably from 1 hour to 36 hours, more preferably from 12 hours to 24 hours. Usually, step a) is carried out until a homogeneous reaction medium is obtained.
  • step a) the silylated biomolecule and the base or the acid are further contacted with a second silylated biomolecule of different nature. Condensation occurs between two silylated biomolecules of different nature, leading to a hydrogel comprising two different biomolecules.
  • Said second silylated biomolecule generally carries an alkoxysilane function.
  • Said second silylated biomolecule typically has the following formula (IV):
  • M is a biomolecule
  • Y is a linker group between the biomolecule and the silane
  • R 4 , R5 and R 6 each independently represent a CrC 6 alkyl group.
  • the second silylated biomolecule is preferably a silylated polysaccharide, in particular a silylated cellulose derivative, such as silylated cellulose, silylated hydroxyethylcellulose (H EC) or silylated H PMC.
  • a silylated polysaccharide in particular a silylated cellulose derivative, such as silylated cellulose, silylated hydroxyethylcellulose (H EC) or silylated H PMC.
  • the proportion of the two silylated biomolecules can vary to a large extent, for example 100 parts by weight of a first silylated biomolecule can be used for 1 part by weight of a second silylated biomolecule in step a), or the same weight for both silylated biomolecules can be used.
  • the proportions and the nature of the two silylated biomolecules By varying the proportions and the nature of the two silylated biomolecules, the structure and nature of the hydrogel can easily be changed and adapted depending on which further use of the hydrogel is searched for, and which biophysical, biological, physical and chemical properties are required for that use.
  • the silylated biomolecule in step a), is a silylated peptide or a silylated protein and the second silylated biomolecule is based on any biomolecule.
  • the silylated biomolecule is a silylated peptide or a silylated protein and the second silylated biomolecule is a silylated polysaccharide, in particular a silylated cellulose derivative, such as silylated cellulose or silylated HPMC.
  • step a) comprises contacting:
  • silylated collagen with silylated HPMC (as second silylated biomolecule) (leading to a hydrogel containing HPMC and collagen),
  • silylated hyaluronic acid with silylated HPMC (as second silylated biomolecule) (leading to a hydrogel containing HPMC and hyaluronic acid)
  • silylated pectin with silylated hyaluronic acid (as second silylated biomolecule) (leading to a hydrogel containing pectin and hyaluronic acid).
  • the second silylated biomolecule has been prepared according to process 1 or 2, wherein the biomolecule of the second silylated biomolecule is of any nature (for example, silylated HPMC can be the second silylated biomolecule, although the procedure of process 1 or 2 is followed).
  • the second silylated biomolecule has not been prepared according to the processes according to the invention.
  • the second silylated biomolecule has been prepared from 3-glycidoxypropyltrimethoxysilane (GPTMS), as described in Bourges et al. Advances in Colloid and Interface Science 99, 215-228, 2002, and the second silylated biomolecule has the following formula (V):
  • M is a biomolecule and Y' is -0-, -NH- or -(CO)O-.
  • Y' is respectively -0-, -NH- or -(CO)O-.
  • step a) the silylated biomolecule and the base are further contacted with two or more other silylated biomolecules of different nature.
  • a hydrogel comprising at least three biomolecules is thus obtained.
  • step b) of the process for the preparation of a hydrogel is preferred.
  • Step b) usually lasts from 1 min to 3 days, preferably from 20 min to 24 hours. Generally, step b) is carried out until the reaction medium is unable to flow. Rheological experiments can be carried out to determine exactly the gelling time.
  • a buffering agent or an isotonic solution is added during step b), for example 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid (HEPES).
  • HEPES 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid
  • the use of buffering agent or the isotonic solution leads to a reaction medium the pH of which is around 7.4, i.e. physiological pH.
  • step b) the pH of the aqueous medium is adjusted to a pH of between 4 and 1 1 , preferably 5 to 10, more preferably 6 to 8, more preferably from 7 to 7.4.
  • cells can be incorporated in the medium.
  • cells are added during step b).
  • An hydrogel advantageously comprising cells can be obtained.
  • an active principle can also be incorporated in the medium.
  • an active principle is added during step b).
  • a hydrogel advantageously comprising an active principle can be obtained, which will be able to release said active principle.
  • steps a) and b) of the process for the preparation of a hydrogel are carried out in sterile conditions, in particular when the further intended use of the hydrogel is for in vivo or in vitro applications, in particular in vivo applications.
  • the invention relates to the hydrogel obtainable by the process as described above.
  • the biophysical, biological, physical and chemical properties of the hydrogel can advantageously be modulated by varying the proportion and the nature of the silylated biomolecule comprised therein.
  • the hydrogel can advantageously be easily injected through syringes.
  • the hydrogel is self-hardening.
  • the hydrogel crosslinks by itself at physiological pH, and can therefore be used in tissue engineering.
  • the hydrogel is also biodegradable, in particular by enzymatic methods.
  • a hydrogel containing hyaluronic acid is degradable by hyaluronidase
  • a hydrogel containing collagen is degradable by collagenase.
  • the hydrogel obtained promotes cell adhesion.
  • Hydrogels containing HPMC and another biomolecule promote better cell adhesion than HPMC-based hydrogel.
  • hydrogel containing two different biomolecules are particularly preferred.
  • the preferred hydrogel are the one comprising the following biomolecules association:
  • the invention concerns the hydrogel as a biological tissue substitute, for example as cartilage-like tissue substitute, bone substitute, heart tissue or skin substitute
  • a biological tissue substitute for example as cartilage-like tissue substitute, bone substitute, heart tissue or skin substitute
  • the hydrogel for its use as a biological tissue substitute, the use of the hydrogel for the preparation of a tissue substitute, and the therapeutic treatment method comprising the use of the hydrogel as tissue substitute are also subject matters of the present invention.
  • the invention relates to a composition
  • a composition comprising a hydrogel as described above in combination with a pharmaceutically acceptable vehicle.
  • the composition may also further comprise an active principle.
  • the invention concerns the use of said composition for the release of an active principle.
  • the composition for its use for the release of active principle, the use of the composition for the preparation of drug releasing an active principle, and the therapeutic treatment method comprising the use of the release of active principle to release active principles, are also subject matters of the present invention.
  • HPMC-Si silylated HPMC
  • the desired lyophilized polyose, protein or peptide was suspended into anhydrous acetonitrile at a total weight ratio of 10-15%, 3-4%, and 0.5-1 .5% respectively.
  • At least one equivalent of triethylamine per function to modify (OH or NH 2 ) was added to the suspension.
  • a mechanical stirring and a nitrogen (or argon) bubbling was applied for at least 20 min before the addition of the silylated reagent, which might contain at least one alkoxysilane group and one isocyanate function (for example 3- isocyanatopropyltriethoxysilane).
  • the circulation of inert gas and the stirring were maintained at ambient temperature (20-25°C) for several days, depending on the amount of the starting materials (e.g.
  • Method A one or more of the desired silylated compounds obtained by the procedure described above was poured into a 0.2 M sodium hydroxide solution at a total weight percentage of 1 to 6. After one night of mechanical stirring, the resulting viscous solution or suspension was transferred into a regenerated cellulosic dialysis tubing of MWCO 6-8000 previously rinsed with a 0.09 M sodium hydroxide solution. The basic solution/suspension was washed with 19 volumes of a 0.09 M sodium hydroxide solution for 18 hours, and then with 20 volumes of a new 0.09 M sodium hydroxide solution for 2 hours. The final pH of the silylated macromolecule solutions was 12.4. Also, one or more of these solutions can be mixed together at various ratios. A classical example was to mix 3 volumes of a 3 wt% silylated biomolecule solution with 1 volume of a 1 to 6 wt% second silylated biomolecule solution.
  • Method B The second and additionals silylated compounds were directly added on the solid state into a basic macromolecule solution prepared as above (typically
  • the basic solution can be sterilized under 254nm UV irradiation for 15min.
  • EXAMPLE 3 Enzymatic degradation assays of hydrogels prepared from silylated biomolecules all obtained by the process according to the invention To 1 .5 ml of hydrogel prepared as above is added either 1 .5 ml of HBSS (Hank's Buffered Salt Solution) alone, either 1 .5 ml of HBSS containing 3 mg of collagenase, either 1 .5 ml of HBSS containing 1 ,5 mg of hyaluronidase. The mixtures were incubated at 37°C.
  • the following table shows if a degradation is obtained by adding collagenase (C) or hyaluronidase (H) to the hydrogel.
  • EXAMPLE 4 Enzymatic degradation assays of hvdrogels prepared from one silylated biomolecule obtained by a process according to the literature, and optionally from another silylated biomolecule obtained by the process according to the invention.
  • hydrogels made with the silylated HPMC obtained by an antecedent silanization protocol (see Bourges et al. (Advances in Colloid and Interface Science 99, 215-228, 2002) which was basically as followed: heptane/1 -propanol, NaOH pellets, 3- glycidoxypropyltrimethoxysilane, heating at 80 °C for 3 hours, quenching with frozen acetic acid, washing with water/acetone, and lyophilisation.
  • Coll-Si, HA-Si and Pec-Si were obtained by the process according to the invention as illustrated in example 1 .
  • Examples 3 and 4 show that the presence of biomolecules such as collagen, hyaluronic acid, or pectine (a 1 -4 glycosidic link) within the HPMC ( ⁇ 1 -4 glycosidic link) based hydrogels induces enzymatic degradation properties.
  • biomolecules such as collagen, hyaluronic acid, or pectine (a 1 -4 glycosidic link) within the HPMC ( ⁇ 1 -4 glycosidic link) based hydrogels induces enzymatic degradation properties.
  • EXAMPLE 5 In vitro assays - cells morphology and adhesion ⁇ Example of protocol for 2D culture :
  • the hydrogels were prepared as described previously, and before their gelation time was reached, 0.3 ml of each mixture was directly poured into a well of a 24-multi wells plate with ultra-low attachment surface. Once the hydrogels were well reticulated, 0.5 ml of classical culture medium was added per well and left over at least a night so it can diffuse within the hydrogel. In each well the culture medium was then replaced by 0.5ml of culture medium containing about 20.000 cells (e.g. MC3T3). The cells morphology and viability were evaluated by "live&dead” assays and optical microcopy analysis (alive cells in green and dead cells in red). The culture medium was changed every 2 days and the observations occurred generally at 5h, 24h, 48h, 7 days and sometimes more.
  • the hydrogels were prepared as described previously, and before their gelation time was reached, the amount of the hydrogel was equally divided between the 2 syringes used to make the mixture. Few ⁇ of culture medium containing the cells were introduced into one of the syringe with a pipette. The cells were dispersed into the hydrogel by connecting the 2 syringes with a luer-lock connector. The final concentration of cells was about 1 .10 6 cells per ml of hydrogel. Once homogenized, 0.3 ml of the mixture was poured into a well of a 24 well plate, and one or two hours later, 0.5 ml of culture medium was added. The culture media was changed every two days, and the cells morphology and viability were evaluated in the same fashion than the 2D cultures.

Abstract

L'invention concerne : une biomolécule silylée ayant la formule suivante (I) : - le procédé de préparation d'une biomolécule silylée de formule (I), - l'utilisation d'une biomolécule silylée de formule (I) pour fonctionnaliser la surface d'un support, - un procédé de préparation d'un hydrogel à l'aide d'une biomolécule silylée de formule (I), -l'hydrogel pouvant être obtenu par ledit procédé, - ledit hydrogel en tant que substitut de tissu biologique, - une composition comprenant ledit hydrogel dans un véhicule pharmaceutiquement acceptable, - ladite composition pour la libération du principe actif.
PCT/EP2011/050981 2010-01-25 2011-01-25 Biomolécules silylées WO2011089267A1 (fr)

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US13/574,970 US9285360B2 (en) 2010-01-25 2011-01-25 Silylated biomolecules

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WO2017009230A1 (fr) 2015-07-10 2017-01-19 Universite De Montpellier Nouveaux materiaux optiques fonctionnalises
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FR3038609A1 (fr) * 2015-07-10 2017-01-13 Centre Nat De La Rech Scient (Cnrs) Nouveaux hydrogels de structure silylee et procede d'obtention
WO2017009200A1 (fr) * 2015-07-10 2017-01-19 Universite De Montpellier Nouveaux hydrogels de structure silylée et procédé d'obtention
WO2017009230A1 (fr) 2015-07-10 2017-01-19 Universite De Montpellier Nouveaux materiaux optiques fonctionnalises
EP3896048A1 (fr) 2020-04-17 2021-10-20 Institut National De La Sante Et De La Recherche Medicale - Inserm Formulation comprenant un ciment phosphocalcique et un hydrogel physique et/ou covalent de polysaccharides, imprimable et ayant des propriétés mécaniques ductiles pour la régénération/réparation osseuse
WO2021209616A1 (fr) 2020-04-17 2021-10-21 Institut National De La Sante Et De La Recherche Medicale (Inserm) Formulation comprenant un ciment phosphocalcique et un hydrogel physique et/ou covalent de polysaccharides, imprimable et présentant des propriétés mécaniques ductiles pour la régénération osseuse/réparation osseuse
WO2022053875A1 (fr) 2020-09-09 2022-03-17 Teoxane SA Hydrogel comprenant un polysaccharide reticule et silyle et son procede d'obtention
WO2023198922A1 (fr) 2022-04-15 2023-10-19 Teoxane SA Procede de preparation d'un hydrogel comprenant un polysaccharide silyle reticule
FR3134577A1 (fr) 2022-04-15 2023-10-20 Teoxane SA Procede de preparation d’un hydrogel comprenant un polysaccharide silyle reticule

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EP2529226A1 (fr) 2012-12-05
US20130004460A1 (en) 2013-01-03

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